Selective inhibition of human leukocyte elastase and bovine alpha-chymotrypsin by novel heterocycles

A number of N-arylbenzisothiazolinone 1,1-dioxides have been synthesized and examined for inhibitory activity against human leukocyte and porcine pancreatic elastase (EC 3.4.21.11), bovine alpha-chymotrypsin (EC 2.4.21.1), human leukocyte cathepsin G (EC 3.4.21.20), and bovine trypsin (EC 3.4.21.4). They are potent, selective, competitive inhibitors of human leukocyte elastase and chymotrypsin. The inhibitory capacity of these compounds is directly related to the electron-withdrawing capability of the aryl substituents. When sufficiently activated, the amide bond in the heterocyclic ring can be cleaved by the enzyme, resulting in inhibition which is highly specific. The most potent inhibitor of hummotrypsin. The inhibitory capacity of these compounds is directly related to the electron-withdrawing capability of the aryl substituents. When sufficiently activated, the amide bond in the heterocyclic ring can be cleaved by the enzyme, resulting in inhibition which is highly specific. The most potent inhibitor of human leukocyte elastase, the 2,4-dinitrophenyl derivative, has a Ki of 2.16 microM with elastase and 0.77 microM with chymotrypsin. This study demonstrates that it is possible to design specificity into non-peptide, low molecular weight serine protease inhibitors, which may have considerable pharmacologic potential.